This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Spontaneous damage to the four bases of DNA is a major cause of the mutations that give rise to cancer. Most of these genetic lesions are corrected by a pathway known as base-excision DNA repair (BER). The key components of BER are DNA glycosylases, enzymes that scan the genome in search of particular kinds of base damage, then initiate the repair process by catalyzing excision of the damaged base from the DNA backbone. The long-term goals of our studies are to understand the precise reaction pathways that they utilize. A comprehensive, fundamental understanding of DNA damage recognition and removal represents the solution to a major aspect of the tumorigenesis puzzle. In the proposed studies, we will focus on the detailed reaction pathway of base-excision repair by the DNA glycosylase, human Ogg1 protein which repairs 8-oxoguanine bases in DNA. There is an ample body of work in the literature on the structural biology of substrate recognition and catalysis by DNA glycosylases, especially hOgg1. In the proposed work here, we are trying to structurally characterize early intermediates in the reaction pathway of hOgg1 where it is sampling damaged DNA. By designing suitable mutants and using a covalent trapping strategy, we are able to trap the enzyme in different states of the catalytic pathway. By obtaining high resolution structures of these intermediates, we aim to understand the different components of the entire catalytic pathway. References: Nat Struct Biol. 2003 Mar;10(3):204-11 Biochemistry. 2003 Feb 8;42(6):1564-72. Nature. 2000 Feb 24;403(6772):859-66

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR012408-11
Application #
7602279
Study Section
Special Emphasis Panel (ZRG1-PC (02))
Project Start
2007-07-01
Project End
2008-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
11
Fiscal Year
2007
Total Cost
$2,648
Indirect Cost
Name
Brookhaven National Laboratory
Department
Type
DUNS #
027579460
City
Upton
State
NY
Country
United States
Zip Code
11973
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